Diuretics and Dehydrants

Zheng Zhang
Department of Pharmacology
School of Pharmaceutical Sciences
Central South University

Part I

Diuretics

Drugs inducing a state of increased urine flow

are called diuretics

Actions:
1. Increase the volume of urine
2. Change the ionic composition and pH of
the urine and blood
Excretion of Water and Electrolytes

I. Overview

a) Tubule fluid ( )
Source: filtration of plasma entering the kidney to the
Bowmans capsule
Components: glucose, sodium bicarbonate, amino acid,
other organic solutes, electrolyte (Na+, K+ and Cl-),
and low molecular weight plasma components

(1~2 )

180

Tubule fluid 180 L/day

Urine Volume 1.5 L/day

b) Factors determine urine formation

Glomerular filtration ( )
Reabsorption ( ) and excretion ( ) of
renal tubules ( )
GFR excretion

Reabsorption
Reabsorption

GFR

excretion

Urine flow increase

Tubular secretion
Larger molecules
Potassium, phosphate,
Hydrogen, Ammonium

Tubular reabsorption
Small molecules
Water
Glucose, amino acids,
sodium, chloride,
calcium, bicarbonate

c) Functional zones of nephrone

I.

Proximal convoluted tubule (

II.

Descending limb of Henles loop ( )

III.

Ascending limb of Henles loop ( )

IV.

Distal convoluted tubule ( )

V.

Collecting duct tubule ( )

1. Proximal convoluted tubule

Location: kidney cortex
Function: reabsorption of almost all of glucose,
and other organic solutes, amino acids, 85%
sodium bicarbonate, 40% sodium chloride,
and 40% water
Acid secretory system: uric acid, diuretics,
antibiotics, etc
Carbonic anhydrase (CA)

Lumenurine
Na+/H+
Exchanger

Interstitiumblood

Proximal
convoluted tube

Na+
H+ + HCO3- ATP

N
HCO3- + H+

+
a

H2CO3
+

CA

H2O + CO2
ClCl--baseExchanger

K+
HCO3-

H2CO3
CA
CO-2 + H2O
Base-

Bicarbonate
Reabsorption

CO2
CA inhibitor

2. Thin descending limb of Henles loop

Location: medullar ( ), with hypertonic
medullary interstitium ( )
Function: water highly permeable and reabsorbed
by passive absorption

Water channel or aquaporin (AQP)

Specific channel for water permeability

Widely distributed: kidney, lung, bronchia,
sweating gland, and reproductive system
Play an important in the reabsorption of water in
the thin descending limb of Henles loop
Deficiency results in diseases, e.g. nephrogenic
diabetes , insipidus ( )

3. Thick ascending limb of Henles loop

Location: Both medullar and cortex
Characteristic: Impermeable to water
Function: NaCl reabsorption (35% filtered sodium),
diluting ( ) of tubular fluid (diluting segment),
medullary hyper-tonicity ( ) and
concentration ( ) of urine

Loop
Lumendiuretics
urine
-

Thick
ascending
limb
Na+

Na
K+
2 Cl+

(+)
Potential
Mg2+, Ca2+

Interstitiumblood
ATP
K+

K+

K+
Cl-

4. Distal convoluted tubule

10% filtered NaCl is reabsorbed

Ca2+ is reabsorbed actively by way of Ca2+

channels in the lumenal membrane and the
basolateral Na+-Ca2+ exchanger

Relative impermeable to water

Further dilution of tubular fluid

Lumenurine
N

+
a

Cl

Interstitiumblood

Na+
ATP
K+

Ca2+

Diuretics
(Thiazide)

Distal
convoluted
tubule

Ca2+

Na+

R PTH

5. Collecting tubule

2-5% filtered NaCl is reabsorbed

Na+ reabsorption in principle cells ( )

results in K+ excretion and negative
potential in lumen ( ), Cl- is
reabsorpted in by intercalated cells (
)

Water highly permeable: ADH increases

water permeability through water channel

Lumenurine

Collecting
tubule

Interstitiumblood

Principal cell
Na+

K+

_ N+
a

Aldosterone

ATP
K+
R ADH

H2O
AQP
Intercalated
ATP
cell
+
H
HCO3-

Potassium-sparing
diuretics
Cl-

II. Classification of Diuretics

1. High efficacy diuretics ( ):

Act on thick ascending limb of Henle (

) in the cortex and medullar, e.g.
furosemide ( ), ethacrynic acid (
), and bumetanide ( )

2. Moderate efficacy diuretics

( ):

Act on thick ascending limb of Henle in the

cortex and early distal convoluted tubule
( ), e.g. thiazides ( ) and
chlortalidone ( )

3. Low efficacy diuretics (

):
Act on distal convoluted tubule (
) and collecting tubule ( ), e.g.
spironolactone ( ), triamtrerene (
), and amiloride ( )
proximal convoluted tubule ( ) ,
e.g. acetazolamide ( )

III. Commonly used diuretics

CA Inhibitors
Proximal tubule

Loop Diuretics
Loop of Henle

Thiazides
Distal tubule

K+-sparing diuretics
Collecting tubule

A. High efficacy diuretics

1. Loop diuretics

Agents: furosemide ( ),

Site of action: ascending limb of Henles

loop

Not limited by acidosis ( )

 Na+-K+-2Cl- cotransporter

NaCl reabsorption

Diluting function
Concentration function

K+ recycle
Lumen positive
potential
Ca2+ and Mg2+
reabsorption

Induce renal prostaglandin G (PG)

synthesis:
Renal Vasodilation and redistribution of
blood flow
Decrease in renin release
Increase in venous capacitance

Pharmacokinetics

Quickly absorbed

Eliminated by renal secretion and glomerular

filtration, t1/2 = 1 h, depends on renal function

Diuretic effects correlate with urinary excretion

Clearance reduced by indomethacin ( )

and probenecid ( )

Therapeutic uses
1. Acute pulmonary and intracranial edema
( ):

An efficient and prompt therapy for acute

pulmonary
Relieve intracranial edema, especially
appropriate in patients with CHF

2. Other edematous status ( ):

Caused by heart, renal or hepatic disease

3. Acute and chronic renal failure (

):
Increase urine volume and K+ excretion;
Flush out intratubular casts and ameliorate
obstruction
Do not delay the progression of renal failure
4. Hypercalcemia ( ):
The loop of Henle is an important site of
calcium reabsorption
Administration of saline with loop diuretics
increase Ca2+ excretion

5. Ameliorate excretion of toxic chemicals

( ):

Detoxification of drugs excreted by the kidney,

e.g. long-acting barbitals, salicylates, bromide
( ), fluoride ( ) and iodide ( )
Saline should be administered simultaneously

Adverse effects
1. Water and electrolyte disorder (
): Hypovolemia ( ), hypokalemia (
), hyponatremia ( ), hypokalemia
alkalosis ( ), and hypomagenesemia
( , chronic use)
2. Ototoxicity ( ):

Dose-related hearing loss, reversible

Permanent deaf: ethracrynic acid ( )
Increased with renal insufficiency or other ototoxic drugs
combination

3.

Hyperuricemia ( ):
Uric reabsorption
Attack of gout ( )

4.

Others:
Nausea, vomiting, gastro-intestinal bleeding, allergic
reaction , cross-reactivity with sulfonamides (
)

Actions of loop diuretics

B. Moderate efficacy diuretics

Thiazides

Agents: hydrochlorothiazide ( )

Location of action: distal convoluted

tubule

Contain sulfonamide group

Actions and mechanisms

1. diuresis: mild and permanent
Na+-Cl- cotransporter
Parathyroid Hormone
PTH

Na+ and Clexcretion

Na+-K+
exchange

Na+-Ca2+
exchange

K+ excretion

Ca2+
Reabsorption

2. Anti-diuresis
Na+ and Cl- excretion
Plasma osmolarity
Reduce polydipsia (
)
Urine volume

3. Hypotensive effect

Early stage: diuresis and decrease in blood volume

Late stage: vasodilation of peripheral vasculature

Pharmacokinetics

Completely absorbed, onset of action in

1~2 h, t1/2 = 4~6 h

Chlorthiazide ( ) is less lipidsoluble, absorbed slowly and long-acting

Competition for organic acid secretory

system, decrease uric acid excretion

Therapeutic uses
1. Edema:

Useful in edema with various causes

Higher degree of response in mild and moderate
edema
Efficacy correlates with degree of renal damage in
nephrogenic edema ( )

2. Hypertension

First line hypotensive agents

In combination with other hypotensive agents

3. Other diseases
Nephrotic insipidus and
pituitary insipidus which is not responsive
to ADH
Nephrolithiasis ( ) due to
hypercalciuria ( )

Adverse effects
1. Electrolyte disorder ( ):
Hypokalemia, hyponatremia,
hypomagenesemia, and hypochloremia
alkalosis

2. Hyperuricemia ( ):
Extracellular fluid volume Uric acid
reabsorption

3. Metabolic change: hyperglycemia and

hyperlipidemia:

Hyperglycermia in patients with diabetic or

abnormal glucose tolerance test

Increase cholesterol and low density lipoproteins

4. Allergic reaction:
Cross-reactive with sulfonamides

C. Low efficacy diuretics

A. Potassium-sparing diuretics:
a)

b)

Direct antagonism of mineralocorticoid receptors,

e.g. spironolactone ( )
Inhibition of Na+ flux through ion channels, e.g
triamterene ( ) and amiloride (
)

B. Carbonic anhydrase (CA) inhibitor: e.g.

acetazolamide ( )

Spironolactone or Antisterone ( )
Sites of action:

Cortical collecting tubule and late distal convoluted

tubule

Actions and mechanisms

Competitive antagonist of aldosterone
Reduce intracellular formation of active
metabolites of aldosterone
Na+ reabsorption, K+ and H+ secretion

Triamtrerene and Amiloride

Action: Increase Na+ excretion and K+ retention
Sites of action: Late distal convoluted tubule and the
collecting tubule

Mechanisms of action
Na+ channel activity Na+- K+ exchange
and Na+ reabsorption lumen negative
position K+ excretion diuresis
B. Inhibit Na+-H+ and Na+-Ca2+ antiporters (
) H+ and Ca2+ excretion (amiloride at
high concentrations)

Therapeutic uses
1. Refractory edema secondary to

hyperaldosteronism:
Edema caused by hepatic cirrhosis and nephron
syndrome

2. Chronic congestive heart failure:

A.

Diuresis and increase in Na+ excretion

B.

Amelioration of other conditions

Acetazolamide ( )
Carbonic anhydrase (CA)
Proximal
tubule
HCO and Na
reabsorption
3

Ciliary
body
HCO secretion
3

Aqueous
humor

Choroid
plex

HCO3secretion
Cerebrospinal
fluid

Therapeutic uses
1.

Glaucoma ( ):
Decrease the rate of aqueous formation
Management of several forms of glaucoma

2. Acute mountain sickness ( ):

Symptoms of acute mountain sickness:

weakness, dizziness, headache, lifethreatening pulmonary and cerebral edema

decrease cerebrospinal fluid

3. Urinary alkalization ( ):

Enhance the excretion of uric acid, and

weak acid substances (e.g. Aspirin)

4. Metabolic alkalosis ( ):
a) Alkalosis due to excess use of diuretics
in chronic heart failure
b) Metabolic alkalosis secondary to
respiratory acidosis

Part II

Dehydrants ( )
Osmotic diuretics ( )
1. Tissue dehydration ( ): increase
osmolarity of plasma
2. Osmotic diuresis: increase water
and ions excretion

Agents:
Mannitol ( )
Sorbitol ( )
Hypertonic glucose (
)
Urea ( )

Characteristics:
1.

Not penetrated into tissues through capillary

2.

Do not undergo metabolism in the body

3.

Could be filtrated by glomerulus

4.

Without any important tubular reabsorption

Mannitol (
)
Action and therapeutic uses:n
1.

Dehydration: reduce intracranial and intraocular

pressure; osmotic diarrhea and
elimination of
toxins from GI tract

2. Diuretics: Prevention of acute renal failure

20% solution for venous injection or dropping

Adverse reactions and contraindications

1.

Headache, lethargy ( ), and mental confusion

( ) occur rarely;

2.

Sex hormonal effects

3.

Chronic use causes hyperkalemia renal

failure

Pharmacokinetics
Triamtrerene:

Metabolized in the liver

Active metabolites and final metabolites cleared by
the kidney
t1/2 = 4.2 h

Amiloride:
Cleared by the kidney, t1/2 = 21 h

Therapeutics uses: refractory edema, in

combination with other diuretics
Adverse effects: rare
Nausea, vomitting, diarrhea, drowsiness
Chronic uses causes hyperkalemia
In combination with indomethacin: acute renal

failure